It is well known to provide pharmaceutically active substances for oral administration in the form of tablets, pills or capsules. The tablet, pill or capsule is generally swallowed with water so that the pharmaceutically active substance can be absorbed by the gastro-intestinal tract. For some patients, swallowing the tablet, pill or capsule is difficult or impossible; this is particularly the case for pediatric patients and geriatric patients. Similar difficulties are often encountered when trying to administer tablets to non-human animals which may be uncooperative about taking tablets, pills or capsules.
Oral solid pharmaceutical dosage forms which rapidly disintegrate in the mouth and methods for their preparation have been proposed in GB A-1548022 and GB-A-2111423. The solid dosage forms as disclosed comprise an open matrix network carrying the pharmaceutically active substance, with the open matrix comprising a water-soluble or water-dispersible carrier material which is inert towards the pharmaceutically active substance. The solid dosage forms are prepared by the sublimation or removal of solvent from a solution or suspension comprising the pharmaceutically active substance and the carrier material. Sublimation or removal of solvent is preferably carried out by freeze drying. A typical approach is to dose a drug suspension into free form blisters followed by rapidly freezing the suspension and then freeze drying. Freeze drying removes the ice to leave a porous tablet which, when placed on the tongue, disperses in a few seconds. The drug particles are then swallowed with the saliva.
Other methods for preparing oral solid pharmaceutical forms which rapidly disintegrate in the mouth are disclosed in U.S. Pat. Nos. 5,039,540; 5,120,549; and 5,330,763, as well as PCT/JP93/01631 and PCT/US93/12566. Other patents are U.S. Pat. Nos. 4,760,093; 4,760,094; and 4,767,789, and European patent application 94305535.0.
While the solid dosage forms referred to above overcome the problem of swallowing tablets, pills or capsules, the patient will taste the pharmaceutically active substrate as the dosage form disintegrates in the mouth. Many pharmaceutically active substances have a bitter or unpleasant taste making them unsuitable for incorporation into a delivery system that rapidly disperses in the mouth. Sweeteners and flavoring agents can be used to mask the unpleasant taste, but in many instances this is still not sufficient to adequately mask the unpleasant taste.
An alternative approach to masking drugs having a bitter or unpleasant taste is to coat the drug particles with a polymer, for example a water insoluble polymer. The presence of the polymer coating around the drug particle prevents the drug from dissolving in the mouth and thereby avoids the bad taste. However, during production of freeze dried dosage forms, wherein a drug suspension is dosed into free form blisters followed by rapidly freezing of the suspension and freeze drying, drug release tends to occur, which leads to the drug being immediately available when the dosage form disperses in the mouth.
One method of limiting the rate of drug release is to increase the particle size of the coated drug particles. These can be coated more effectively, and also due to a decrease in the surface area compared with smaller particles, will decrease the release rate of the drug. A consequence of the use of large particles however the rapid sedimentation during processing as a suspension, and the resultant variation in the amount of drug per unit.
U.S. Pat. No. 5,384,124 describes a system in which a thick paste is formulated prior to freeze drying to prevent sedimentation of microsphere coated drug particles. The paste also contains amounts of a suspension agent in excess of its solubility limit to help prevent sedimentation of the microspheres during lyophilization. The presence of these additional components leads to a product with a high solids content which generally does not disperse until thirty seconds or longer (sometimes up to 1 to 3 minutes) after administration.
A need exists for improved rapidly disintegrating dosage forms which overcome the disadvantages noted above. In particular, a need exists for a dosage form which does not give rise to a bad taste when taken orally but which provides controlled release of the drug upon swallowing. The present invention provides such improved rapidly disintegrating dosage forms and processes for their preparation by allowing processing of coarse coated particles without affecting the physical properties of the dried units. The invention can also be used to enable processing of coarse uncoated drug material, preventing the need to obtain size reduced material and an additional manufacturing stage.